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Nat Commun. 2015 Oct 29;6:8644. doi: 10.1038/ncomms9644.

CCR2 defines in vivo development and homing of IL-23-driven GM-CSF-producing Th17 cells.

Author information

1
Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
2
Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.
3
Department of Internal Medicine II, University Hospital Regensburg, Regensburg 93042, Germany.
4
Department of Microbiology and Immunology, VIB and University of Leuven, B-3000 Leuven, Belgium.
5
Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
6
Department of Neurosciences, KU-Leuven-University of Leuven, B-3000 Leuven, Belgium.
7
QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
8
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
9
School of Medicine, University of Queensland, Herston, Queensland 4006, Australia.
10
The Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
11
Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia 5005, Australia.

Abstract

IL-17-producing helper T (Th17) cells are critical for host defense against extracellular pathogens but also drive numerous autoimmune diseases. Th17 cells that differ in their inflammatory potential have been described including IL-10-producing Th17 cells that are weak inducers of inflammation and highly inflammatory, IL-23-driven, GM-CSF/IFNγ-producing Th17 cells. However, their distinct developmental requirements, functions and trafficking mechanisms in vivo remain poorly understood. Here we identify a temporally regulated IL-23-dependent switch from CCR6 to CCR2 usage by developing Th17 cells that is critical for pathogenic Th17 cell-driven inflammation in experimental autoimmune encephalomyelitis (EAE). This switch defines a unique in vivo cell surface signature (CCR6(-)CCR2(+)) of GM-CSF/IFNγ-producing Th17 cells in EAE and experimental persistent extracellular bacterial infection, and in humans. Using this signature, we identify an IL-23/IL-1/IFNγ/TNFα/T-bet/Eomesodermin-driven circuit driving GM-CSF/IFNγ-producing Th17 cell formation in vivo. Thus, our data identify a unique cell surface signature, trafficking mechanism and T-cell intrinsic regulators of GM-CSF/IFNγ-producing Th17 cells.

PMID:
26511769
PMCID:
PMC4639903
DOI:
10.1038/ncomms9644
[Indexed for MEDLINE]
Free PMC Article

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